Protein Folding

Co-translational Protein Folding

Summary

Co-translational folding describes the process where a nascent polypeptide begins acquiring its 3D structure while still being synthesized by the ribosome. This vectorial process proceeds from N-terminus to C-terminus.

Key Points

  • 1Folding begins during translation, not after
  • 2Exit tunnel allows α-helix formation inside ribosome
  • 3Rare codons induce pausing for folding time
  • 4Ribosome-associated chaperones protect nascent chains

Unlike refolding experiments in test tubes, cellular protein folding begins during translation, fundamentally changing the folding landscape.

Vectorial Nature of Folding

Co-translational folding is inherently vectorial:

  • Proceeds from N-terminus to C-terminus
  • N-terminal domains can fold completely before C-terminal domains are synthesized
  • Prevents inter-domain misfolding in multi-domain proteins

    • The Ribosomal Exit Tunnel

    The ribosome itself influences folding through its exit tunnel:

  • Approximately 100 Å long and 10-20 Å wide
  • Restricts conformational entropy of the emerging chain

    • - Allows α-helix formation inside the tunnel

  • Small tertiary motifs can begin forming near the exit
  • "Primes" the nascent chain for folding upon exit

    • Translation Kinetics and Folding

    The speed of translation is not uniform and affects folding:

    Codon Usage

    - "Rare" codons induce ribosomal pausing

  • Pauses provide time for emerging domains to fold

    • - Codon optimization (for expression) can disrupt native folding

  • Synonymous mutations can cause misfolding diseases

    • Translational Pausing

    Strategic pauses allow:

  • Domain boundaries to fold independently
  • Chaperone recruitment
  • Proper membrane insertion for membrane proteins

    • Ribosome-Associated Chaperones

    Specialized chaperones associate directly with the ribosome:

    - Trigger Factor (TF): Bacterial, binds ribosome exit site

    - NAC (Nascent chain-Associated Complex): Eukaryotic

    - Hsp70 (Ssb in yeast): Recruited to translating ribosomes

    - SRP (Signal Recognition Particle): For secretory proteins

    Advantages of Co-translational Folding

    - Reduces aggregation by sequential domain folding

  • Allows co-factors to bind before complete synthesis

    • - Enables co-translational membrane insertion

  • Prevents toxic aggregation of incomplete chains
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    Chaperone-Assisted Protein Folding
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    Protein Misfolding and Aggregation